Halo-substituted piperidines as orexin receptor modulators

Abstract

The present application relates to certain halo-substituted piperidine compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is halogen; 
         X′ is H or halogen; 
         Z is NR 2  or O; 
         A is aryl, aroyl, heteroaryl, or heteroaroyl, wherein A is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR a R b , —N(R a )C(O) alkyl, —N(R a )CO 2 alkyl, —N(R a )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR a R b , —SO 2 alkyl, and —SO 2 NR a R b ; wherein R a  and R b  are independently for each occurrence H or alkyl; 
         B is aryl or heteroaryl, wherein B is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR c R d , —N(R c )C(O) alkyl, —N(R c )CO 2 alkyl, —N(R c )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR c R d , —SO 2 alkyl, and —SO 2 NR c R d ; wherein R c  and R d  are independently for each occurrence H or alkyl; 
         E is aryl or heteroaryl, wherein E is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR e R f , —N(R e )C(O) alkyl, —N(R e )CO 2 alkyl, —N(R e )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR e R f , —SO 2 alkyl, and —SO 2 NR e R f ; wherein R e  and R f  are independently for each occurrence H or alkyl; 
         n=1, 2, or 3; 
         R 1  is alkyl; and 
         R 2  is H or alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein A is aryl or heteroaryl. 
     
     
         3 . The compound of  claim 1 or 2 , wherein the compound has the structure of formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of any one of  claims 1-3 , wherein Z is NR 2 . 
     
     
         5 . The compound of any one of  claims 1-4 , wherein R 2  is hydrogen. 
     
     
         6 . The compound of any one of  claims 1-4 , wherein R 2  is methyl. 
     
     
         7 . The compound of any one of  claims 1-6 , wherein X is —F. 
     
     
         8 . The compound of any one of  claims 1-7 , wherein X′ is —F. 
     
     
         9 . The compound of any one of  claims 1-8 , wherein R 1  is C 1-4 alkyl. 
     
     
         10 . The compound of any one of  claims 1-9 , wherein R 1  is methyl. 
     
     
         11 . The compound of any one of  claims 1-10 , wherein A is an optionally substituted monocyclic or bicyclic heteroaryl. 
     
     
         12 . The compound of any one of  claims 1-11 , wherein A is selected from the list consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzoxazolyl. 
     
     
         13 . The compound of any one of  claims 1-12 , wherein A is pyridinyl. 
     
     
         14 . The compound of any one of  claims 1-12 , wherein A is pyrimidinyl. 
     
     
         15 . The compound of any one of  claims 1-12 , wherein A is pyrazinyl. 
     
     
         16 . The compound of any one of  claims 1-12 , wherein A is pyridazinyl. 
     
     
         17 . The compound of any one of  claims 1-16 , wherein A is unsubstituted. 
     
     
         18 . The compound of any one of  claims 1-16 , wherein A is optionally substituted with one or more substituents independently selected from the list consisting of alkyl, alkoxy, and halo. 
     
     
         19 . The compound of any one of  claims 1-16 or claim 18 , wherein A is optionally substituted with one or more substituents independently selected from the list consisting of —F, —Br, —Cl, —CF 3 , methyl, ethyl, and methoxy. 
     
     
         20 . The compound of any one of  claims 1-16 or claim 18 , wherein A is optionally substituted with one or more substituents independently selected from the list consisting of —F, —Br, —Cl, —CHF 2 , —CF 3 , methyl, ethyl, and methoxy. 
     
     
         21 . The compound of any one of  claims 1-16 or claims 18-20  wherein A is monosubstituted. 
     
     
         22 . The compound of  claim 21 , wherein A is substituted with —CHF 2  or —CF 3 . 
     
     
         23 . The compound of  claim 21 , wherein A is substituted with —CF 3 . 
     
     
         24 . The compound of any one of  claims 1-23 , wherein B is an optionally substituted aryl. 
     
     
         25 . The compound of any one of  claims 1-24 , wherein B is an optionally substituted phenyl. 
     
     
         26 . The compound of any one of  claims 1-24 , wherein B is an optionally substituted monocyclic heteroaryl or bicyclic heteroaryl. 
     
     
         27 . The compound of any one of  claims 1-23 or claim 26 , wherein B is selected from the list consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiazolyl, thiophenyl, pyrazolyl, and benzoimidazolyl. 
     
     
         28 . The compound of  claim 27 , wherein B is selected from the list consisting of pyridinyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and benzoimidazolyl. 
     
     
         29 . The compound of any one of  claims 1-23 or claims 26-28 , wherein B is pyridinyl. 
     
     
         30 . The compound of any one of  claims 1-23 or claims 26-28 , wherein B is thiophenyl. 
     
     
         31 . The compound of any one of  claims 1-23 or claims 26-28 , wherein B is oxazolyl. 
     
     
         32 . The compound of any one of  claims 1-23 or claims 26-28 , wherein B is thiazolyl. 
     
     
         33 . The compound of any one of  claims 1-23 or claims 26-28 , wherein B is pyrazolyl. 
     
     
         34 . The compound of any one of  claims 1-23 or claims 26-28 , wherein B is triazolyl. 
     
     
         35 . The compound of any one of  claims 1-23 or claims 26-28 , wherein B is benzoimidazolyl. 
     
     
         36 . The compound of any one of  claims 1-35 , wherein B is optionally substituted with one or more substituents independently selected from the group consisting of an alkyl, halo, alkoxy, and —CN. 
     
     
         37 . The compound of any one of  claims 1-36 , wherein B is optionally substituted with one or more substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, methyl, ethyl, isopropyl, —CF 3 , —CH 2 CF 3 , isopropoxy, and methoxy. 
     
     
         38 . The compound of  claim 37 , wherein B is substituted with one or more methyl. 
     
     
         39 . The compound of any one of  claims 1-38 , wherein B is monosubstituted. 
     
     
         40 . The compound of  claim 39 , wherein B is substituted with methyl. 
     
     
         41 . The compound of any one of  claims 1-40 , wherein E is an optionally substituted phenyl. 
     
     
         42 . The compound of any one of  claims 1-40 , wherein E is an optionally substituted monocyclic heteroaryl. 
     
     
         43 . The compound of any one of  claims 1-40 or 42 , wherein E is selected from the group consisting of triazolyl, tetrazolyl, pyrazolyl, pyridinyl, oxadiazolyl, pyrazinyl, and pyrimidinyl. 
     
     
         44 . The compound of any one of  claims 1-40 or 42 , wherein E is triazolyl. 
     
     
         45 . The compound of any one of  claims 1-40 or 42 , wherein E is tetrazolyl. 
     
     
         46 . The compound of any one of  claims 1-40 or 42 , wherein E is pyrazolyl. 
     
     
         47 . The compound of any one of  claims 1-40 or 42 , wherein E is pyridinyl. 
     
     
         48 . The compound of any one of  claims 1-40 or 42 , wherein E is oxadiazolyl. 
     
     
         49 . The compound of any one of  claims 1-40 or 42 , wherein E is pyrimidinyl. 
     
     
         50 . The compound of any one of  claims 1-49 , wherein E is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, and alkoxy. 
     
     
         51 . The compound of any one of  claims 1-50 , wherein E is optionally substituted with one or more —F, —Cl, —Br, methoxy, methyl, ethyl, —CF 2 H or —CF 3 . 
     
     
         52 . The compound of  claim 51 , wherein E is optionally substituted with one or more —F, —Cl, —Br, methoxy, methyl, ethyl, or —CF 3 . 
     
     
         53 . The compound of any one of  claims 1-52 , wherein E is optionally substituted with one or more methyl or —F. 
     
     
         54 . The compound of any one of  claims 1-53 , wherein E is monosubstituted. 
     
     
         55 . The compound of any one of  claims 1-49 , wherein E is unsubstituted. 
     
     
         56 . The compound of any one of  claims 1-23 , wherein the fragment —B-E has the structure 
       
         
           
           
               
               
           
         
         wherein: 
         Y, independently for each occurrence, represents CH or N; and 
         R 3  represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR g R h , —N(R g )C(O) alkyl, —N(R g )CO 2 alkyl, —N(R g )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR g R h , —SO 2 alkyl, or —SO 2 NR g R h ; wherein R g  and R h  are independently for each occurrence H or alkyl. 
       
     
     
         57 . The compound of  claim 56 , wherein the structure 
       
         
           
           
               
               
           
         
       
       is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         58 . The compound of any one of  claims 1-23 or claims 56-57 , wherein the fragment —B-E has the structure 
       
         
           
           
               
               
           
         
       
     
     
         59 . The compound of any one of  claims 56-58 , wherein R 3  is alkyl or alkoxy. 
     
     
         60 . The compound of any one of  claims 56-59 , wherein R 3  is —CH 3 , —CF 3 , or methoxy. 
     
     
         61 . The compound of any one of the  claims 1-23 or claims 56-57 , wherein the fragment —B-E has the structure 
       
         
           
           
               
               
           
         
       
     
     
         62 . The compound of  claim 61 , wherein R 3  is CN, halo or alkyl. 
     
     
         63 . The compound of  claim 62 , wherein R 3  is —F, —Cl, —CN, or methyl. 
     
     
         64 . The compound of any one of  claims 1-23 , wherein the fragment —B-E forms a hetero-aromatic ring structure of 
       
         
           
           
               
               
           
         
         wherein:
   , independently for each occurrence, represents a single or double bond; 
 W, independently for each occurrence, represents N, S, O, or CH; 
 V represents N or C; and
 R 4  represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR i R j , —N(R i )C(O) alkyl, —N(R i )CO 2 alkyl, —N(R i )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR i R j , —SO 2 alkyl, or —SO 2 NR i R j ; wherein R i  and R j  are independently for each occurrence H or alkyl. 
 
 
       
     
     
         65 . The compound of  claim 64 , wherein the structure 
       
         
           
           
               
               
           
         
       
       is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         66 . The compound of  claim 64 , wherein the structure 
       
         
           
           
               
               
           
         
       
     
     
         67 . The compound of  claim 64 , wherein the structure 
       
         
           
           
               
               
           
         
       
     
     
         68 . The compound of any one of  claims 64-67 , wherein R 4  is C 1-4 alkyl. 
     
     
         69 . The compound of  claim 68 , wherein R 4  is methyl. 
     
     
         70 . The compound of any of  claims 1-3 or 7-69 , wherein Z is 0. 
     
     
         71 . The compound of any of  claims 1-70 , wherein n=1. 
     
     
         72 . The compound of  claim 1 , wherein the compound has a structure of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         m is 1, 2, or 3; 
         R 5  represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR j R k , —N(R j )C(O) alkyl, —N(R j )CO 2 alkyl, —N(R j )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR j R k , —SO 2 alkyl, or —SO 2 NR j R k ; wherein R j  and R k  are independently for each occurrence H or alkyl; and 
         X, X′, Z, B, E, n, R 1  and R 2  are as defined in  claim 1 . 
       
     
     
         73 . The compound of  claim 1 , wherein the compound has a structure of formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         m is 1, 2, 3 or 4; 
         R 5  represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR j R k , —N(R j )C(O) alkyl, —N(R j )CO 2 alkyl, —N(R j )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR j R k , —SO 2 alkyl, or —SO 2 NR j R k ; wherein R j  and R k  are independently for each occurrence H or alkyl; and 
         X, X′, Z, B, E, n, R 1  and R 2  are as defined in  claim 1 . 
       
     
     
         74 . The compound of  claim 1 , wherein the compound has a structure of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         R 6  represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR o R p , —N(R o )C(O) alkyl, —N(R p )CO 2 alkyl, —N(R o )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR o R p , —SO 2 alkyl, or —SO 2 NR o R p ; wherein R o  and R p  are independently for each occurrence H or alkyl; and 
         X, X′, Z, A, E, n, R 1  and R 2  are as defined in  claim 1 . 
       
     
     
         75 . The compound of  claim 1 , wherein the compound has a structure of formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 6  represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR o R p , —N(R o )C(O) alkyl, —N(R p )CO 2 alkyl, —N(R o )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR o R p , —SO 2 alkyl, or —SO 2 NR o R p ; wherein R o  and R p  are independently for each occurrence H or alkyl; and 
         X, X′, Z, A, E, n, R 1  and R 2  are as defined in  claim 1 . 
       
     
     
         76 . The compound of  claim 1 , wherein the compound is compound 185, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         77 . The compound of  claim 1 , wherein the compound is compound 129, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         78 . The compound of  claim 1 , wherein the compound is compound 217, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         79 . The compound of  claim 1 , wherein the compound is compound 264, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         80 . The compound of  claim 1 , wherein the compound is compound 66, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         81 . The compound of  claim 1 , wherein the compound is compound 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         82 . A compound selected from the group consisting of compounds as shown in Table 1, and pharmaceutically acceptable salts thereof. 
     
     
         83 . A pharmaceutical composition comprising (a) a compound of  any of the preceding claims ; and (b) a pharmaceutically acceptable excipient. 
     
     
         84 . A compound of any one of  claims 1-82  or a pharmaceutical composition of  claim 83  for use as a medicament. 
     
     
         85 . A method of treating a disease or disorder mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of  claims 1-82  or a pharmaceutical composition of  claim 83 . 
     
     
         86 . The method of  claim 85 , wherein the disease or disorder is selected from the group consisting of drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, seasonal affective disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, pain, epilepsy, behavior disorder, mood disorder, manic depression, dementia, sex disorder, and psychosexual disorder. 
     
     
         87 . The method of  claim 86 , wherein the drug abuse or addiction is selected from abuse of or addiction to cocaine, opiates, amphetamines, ethanol,  Cannabis /marijuana, or nicotine. 
     
     
         88 . The method of  claim 85 , wherein the disease or disorder is selected from the group consisting of an eating disorder, obesity, alcoholism or an alcohol-related disorder, headache, migraine, gastrointestinal diseases, inflammations, immune-related diseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases, cancer, hypertension, and renal disease. 
     
     
         89 . Use of a compound of any of  claims 1-82  or a pharmaceutical composition of  claim 83 , in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity, and the use of such compounds for treatment of such diseases and disorders. 
     
     
         90 . The use of  claim 89 , wherein the disease or disorder is selected from the group consisting of drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, seasonal affective disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, pain, epilepsy, behavior disorder, mood disorder, manic depression, dementia, sex disorder, and psychosexual disorder. 
     
     
         91 . The use of  claim 90 , wherein the drug abuse or addiction is selected from abuse of or addiction to cocaine, opiates, amphetamines, ethanol,  Cannabis /marijuana, or nicotine. 
     
     
         92 . The use of  claim 89 , wherein the disease or disorder is selected from the group consisting of an eating disorder, obesity, alcoholism or an alcohol-related disorder, headache, migraine, gastrointestinal diseases, inflammations, immune-related diseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases, cancer, hypertension, and renal disease. 
     
     
         93 . Use of a compound of any one of  claims 1-82  or a pharmaceutical composition of  claim 83 , in the preparation of a medicament for treating a disease or disorder in a patient in need thereof. 
     
     
         94 . The use of  claim 93 , wherein the disease or disorder is selected from the group consisting of drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, seasonal affective disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, pain, epilepsy, behavior disorder, mood disorder, manic depression, dementia, sex disorder, and psychosexual disorder. 
     
     
         95 . The use of  claim 94 , wherein the drug abuse or addiction is selected from abuse of or addiction to cocaine, opiates, amphetamines, ethanol,  Cannabis /marijuana, or nicotine. 
     
     
         96 . The use of  claim 93 , wherein the disease or disorder is selected from the group consisting of an eating disorder, obesity, alcoholism or an alcohol-related disorder, headache, migraine, gastrointestinal diseases, inflammations, immune-related diseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases, cancer, hypertension, and renal disease. 
     
     
         97 . A method of modulating the activity of an orexin receptor OX 1 , OX 2 , or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound of any one of  claims 1-82  or a pharmaceutical composition of  claim 83 . 
     
     
         98 . The method of  claim 97 , wherein the contacting is in vitro, ex vivo, or in vivo. 
     
     
         99 . A method of treating a disease or disorder in a patient in need thereof, comprising administering a compound of any one of  claims 1-82  or a pharmaceutical composition of  claim 83 . 
     
     
         100 . The method of  claim 99 , wherein the disease or disorder is selected from the group consisting of drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, seasonal affective disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, pain, behavior disorder, mood disorder, manic depression, dementia, sex disorder, and psychosexual disorder. 
     
     
         101 . The method of  claim 99 , wherein the disease or disorder is selected from the group consisting of an eating disorder, obesity, alcoholism or an alcohol-related disorder, headache, migraine, gastrointestinal diseases, inflammations, immune-related diseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases, cancer, hypertension, and renal disease. 
     
     
         102 . The method of  claim 99 , wherein the disease or disorder is selected from the group consisting of drug abuse or addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, and hypertension. 
     
     
         103 . The method of  claim 100 or 102 , wherein the drug abuse or addiction is selected from abuse of or addiction to cocaine, opiates, amphetamines, ethanol,  Cannabis /marijuana, or nicotine.